Inferences about the environmental influences of parental alcoholism on risk of childhood disorders such as Attention Deficit Hyperactivity Disorder or Conduct Disorder, or Depression, which in turn predict increased offspring risk of alcohol use disorders and associated high-risk behaviors (eg: early onset of alcohol use), have been hindered by a failure to recognize (i) the confounding of genetic effects, and genotype x shared environment interaction effects in the twin design, and (ii) the selection for high risk genetic backgrounds, but reduced environmental risk exposures, in adoption study designs. As an alternative, we propose a children-of- twins study, that builds upon our prior studies of a cohort of young adult Australian twins characterized by a history of heavy drinking and high rates of alcohol problems, in women as well as men. Comparison of outcomes in children exposed to both high genetic and high environmental risk (twin father is alcohol dependent [AD], or twin mother is AD or alcohol abuser [AB]: 'alcoholic'[ALC]), children exposed to reduced environmental risk but varying degrees of genetic risk (twin parent is unaffected, but parent's MZ, DZ female, or DZ male cotwin is alcoholic: 'high risk'), and children from control families (twin parent, and parent's cotwin, both unaffected), will enable us to identify high risk environmental exposures associated with parental alcoholism that are predictive of offspring outcomes, with statistical control for genetic transmission of risk. Intake, 2-yr and in some cases 4-yr follow-up interviews will be conducted with the children's parents (a projected N=1900 parents reporting about 3350 offspring aged 7 yrs and older, as well as about own and partner's history of alcohol use and comorbid disorders) and with male and female offspring aged 11 yrs and older (N=2260), and will be supplemented by intake interviews with co-parents of these offspring (N=1300). Hypotheses will be tested about the pathways by which alcoholism in the parental generation via genetic transmission and/or increased high-risk environmental exposures, is associated with increased risk of psychopathology and other high-risk outcomes in offspring, taking into consideration pre-conception factors I (mate selection), pre-natal risk-factors (maternal smoking and drinking), and post-natal factors (both factors I associated with the presence of an alcoholic parent in the home, and factors such as socioeconomic disadvantage I associated with parental absence or parental past history of ALC). _ERFORMANCE SITE(S) (organization, city, state) Washington University School of Medicine, St. Louis, Missouri Queensland Institute of Medical Research, Brisbane, Australia KEY PERSONNEL. See instructions. Use Start with Principal Investigator. List all other Name Andrew C. Heath, DPhil Anne Glowinksi, MD Michael T. Lynskey, PhD Nicholas G. Martin, PhD Elliot Nelson, MD Theodore Jacob, PhD Wendy Slutske, PhD continuation pages as needed to provide the required information key personnel in alphabetical order, last name first. Organization Washington University Washington University Washington University Queensland Institute of Medical Research, Brisbane, Australia Washington University Palo Alto Veterans Administration University of Missouri, Columbia in the format shown below. Role on Project Principal Investigator Coinvestigator Coinvestigator Project Co-Director Coinvestigator Consultant Consultant Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No PHS 398 (Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Principal Investigator/Program Director (Last, First, Middle): Heath, Andrew C. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,